The influence of maternal antibodies on neonatal intestinal immunity

母源抗体对新生儿肠道免疫的影响

• 批准号: 9677877
• 负责人: Gregory M Barton
• 金额: $ 38.18万
• 依托单位: UNIVERSITY OF CALIFORNIA BERKELEY
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-24 至 2021-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9677877
• 关键词: Address; Adopted; Adult; Antibodies; Antibody Formation; Antibody Response; Antigens; B-Cell Activation; Bacteria; Body Weight; Characteristics; Complement Activation; Defect; Digestion; Disease; Fc Receptor; Gnotobiotic; Goals; Health; Helper-Inducer T-Lymphocyte; Homeostasis; Human; Human Milk; IgG3; Immune; Immune response; Immune system; Immunity; Immunoglobulin G; Immunology; Inflammatory; Inflammatory Response; Intestines; Intuition; Life; Mammals; Maternal antibody; Microbe; Morbidity - disease rate; Mothers; Mucosal Immune Responses; Mucous Membrane; Mus; Neonatal; Newborn Infant; Nutrient; Pathogenicity; Physiology; Play; Role; Systemic infection; T cell response; T-Lymphocyte; Tissues; Work; colonization resistance; commensal bacteria; dysbiosis; enteric pathogen; gut bacteria; human disease; immune function; improved; in utero; intestinal homeostasis; member; microbial; microbiota; microorganism; microorganism antigen; mortality; mouse model; neonatal immune system; neonatal immunity; neonate; offspring; pup; receptor function; response

How the neonatal immune system avoids inflammatory responses during initial acquisition of the microbiota remains unclear. Establishing intestinal homeostasis is particularly challenging for neonates because their immune systems have not fully developed. The goal of this application is to investigate how maternal antibodies instruct the neonatal immune system to limit T cell responses to newly acquired microbial antigens in the intestine. This proposal builds on our discovery that mothers generate T cell-independent IgG2b and IgG3 antibodies reactive with the microbiota and pass these antibodies to their offspring in utero and through breastmilk. Newborn mice that do not receive any maternal antibodies show increased translocation of commensal bacteria across the intestinal barrier, mount inappropriate T cell responses against mucosal antigens, and weigh less for the first few weeks of life. Similar defects are apparent in neonates that only lack maternal IgG2b and IgG3, demonstrating that these isotypes are required to maintain intestinal homeostasis early in life. Remarkably, if neonates are experimentally forced to acquire T-dependent IgG2c antibodies reactive with the microbiota, then they suffer significant mortality and morbidity. Thus, our preliminary results indicate that the type of antibody acquired by neonates from their mothers can dramatically impact health during the first weeks of life. This proposal will determine the mechanism by which different IgG isotypes suppress or enhance responses to the microbiota in neonates. In addition, we will determine whether specific bacteria drive the immune dysregulation observed in the absence of maternal IgG antibodies or when inflammatory IgG isotypes are acquired. Overall, the studies described in this proposal will reveal how microbiota-reactive maternal antibodies regulate neonatal immunity to the microbiota.

新生儿免疫系统如何在初始获取微生物群期间避免炎症反应 仍不清楚。建立肠道稳态对于新生儿来说尤其具有挑战性，因为他们 免疫系统尚未完全发育。该应用程序的目标是调查母亲如何 抗体指导新生儿免疫系统限制 T 细胞对新获得的微生物抗原的反应 在肠道中。该提议建立在我们发现母亲产生不依赖于 T 细胞的 IgG2b 和 IgG3 抗体与微生物群发生反应，并将这些抗体传递给子宫内的后代 母乳。未接受任何母体抗体的新生小鼠显示出易位增加 共生细菌穿过肠道屏障，对粘膜产生不适当的 T 细胞反应 抗原，并且在生命的最初几周内体重减轻。类似的缺陷在新生儿中也很明显，只是缺乏 母体 IgG2b 和 IgG3，证明这些同种型是维持肠道稳态所必需的 在生命的早期。值得注意的是，如果通过实验强迫新生儿获得 T 依赖性 IgG2c 抗体 与微生物群发生反应，然后它们会遭受显着的死亡率和发病率。因此，我们的初步结果 表明新生儿从母亲那里获得的抗体类型可以极大地影响健康 在生命的最初几周。该提案将确定不同 IgG 同种型的机制 抑制或增强新生儿对微生物群的反应。此外，我们将确定是否具体 在母体 IgG 抗体不存在或缺乏母体 IgG 抗体的情况下，细菌会导致免疫失调 获得炎症性 IgG 同种型。总体而言，本提案中描述的研究将揭示如何 微生物群反应性母体抗体调节新生儿对微生物群的免疫力。